Structural basis of SIRT7 nucleosome engagement and substrate specificity.

ABSTRACT: Chromatin-modifying enzymes target distinct residues within histones to finetune gene expression profiles. SIRT7 is an NAD⁺-dependent deacylase often deregulated in cancer, which deacetylates either H3 lysine 36 (H3K36) or H3K18 with high specificity within nucleosomes. Here, we report structures of nucleosome-bound SIRT7, and uncover the structural basis of its specificity towards H3K36 and K18 deacylation, combining a mechanism-based cross-linking strategy, cryo-EM, and enzymatic and cellular assays. We show that the SIRT7 N-terminus represents a unique, extended nucleosome-binding domain, reaching across the nucleosomal surface to the acidic patch. The catalytic domain binds at the H3-tail exit site, engaging both DNA gyres of the nucleosome. Contacting H3K36 versus H3K18 req

SUBMITTER: Moreno-Yruela C 

PROVIDER: S-EPMC11790868 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature